In recent years, in line with the global warming trend, the average temperature in Japan is steadily increasing, and the records of the highest temperature and the number of sultry nights (which are defined as the nights when the temperature does not fall below 25° C.) in summer are being broken every year. The temperature increase in summer is remarkable especially in cities. The incidence of heat illness in sports, manual labor, or daily life has been reported (Miyake et al., Nihon Kyukyu Igakukai Zasshi (Journal of Japanese Association for Acute Medicine), 19: 309-21 (2008)). Investigation on heat illness patients who were treated in emergency medical care centers across the country from June to August in 2006 revealed that the fatality rate is significantly high in patients with a body temperature of 40° C. or more. Heat illness with poor prognosis may lead to a very critical condition, which may result in death with multiple organ failure.
In order to prevent or counteract heat illness, the Ministry of Environment has issued Netchusho Kankyo Hoken Manual (the Environment Health Manual on Heat Illness).
There is also a report that the death toll due to heat illness is increasing not only in humans but also in livestock animals such as cattle, pigs, chickens (the Sankei Shimbun dated Sep. 3, 2010). During the period from July 1 to August 15 in 2010, the number of livestock animals that died or abandoned due to heat stroke etc. reached 959 dairy-cattle, 235 beef-cattle, 657 pigs, 289,000 broiler chickens and 136,000 egg-laying chickens (Kumamoto Prefecture Chuokaho News vol. 5, August (2010)). Minor health problems in livestock animals such as cattle, pigs, and chickens will affect their market values. If livestock animals died, the economic loss will reach several million yen per animal. In terms of companion animals such as dogs and cats, minor health problems in the animals will hugely affect the owners' daily lives. Thus health care of the above animals is a huge social problem.
In addition, the productivity and quality of livestock animals are known to deteriorate due to high air temperature and high humidity in summer. Under summer heat stress, reduction occurs in sperm production, egg maturation, fetal development, fetal growth, placenta maturation, etc., and also in the pregnancy rate (Nabenishi H. et al., J. Reprod. Dev. (2001) April 9, E. Pub.). Further, due to continuous high air temperature, reduction occurs in body weight gain, the amount of milk secretion, and the egg laying rate, and also in the milk quality (milk fat percentage) and the meat quality (Chikyu Ondanka Ni Taio shita Norin Suisan Kenkyu Kaihatsu Vision, p. 10 (March 2010, Agriculture, Forestry and Fishery Department, Yamagata Prefecture)). The reduction in the productivity of domestic fowls and livestock animals under summer heat is closely related to increase in the body temperature (Nonaka et al., Chikyukankyo (2009) 14: 215-222). Therefore, lowering the body temperature of livestock animals during the summer heat period is expected to improve the productivity of the livestock animals.
Animals have thermoregulatory functions such as perspiration and can maintain a constant body temperature regardless of changes in air temperature and weather. However, when high air temperature and high humidity conditions continue, or when the thermoregulatory functions are impaired, the body temperature of an animal may abnormally increase. In such cases, it is necessary to immediately notice the animal's unusual signs and treat the animal to lower the body temperature. In cases where increase in air temperature is predicted, lowering the body temperature of an animal in advance may be useful in maintaining good health of the animal. Further, even when the body temperature of an animal is already in the course of increasing, suppression of the increase enables early treatment and prevents the body temperature from reaching the lethal level. In particular, in the case of heat stroke, the body temperature of an animal sometimes reaches 40° C., which will increase the risk of death. Therefore, there has been a great demand for a means to prevent heat illness including heat stroke.
Ghrelin is a hormone discovered from the stomach in 1999 and is a peptide composed of an amino acid sequence consisting of 28 residues. The amino acid sequence has a very unique chemical structure in which the third amino acid from the N-terminus is acylated with a fatty acid (Non Patent Literature 1 and Patent Literature 1). Ghrelin is an endogenous brain-gut hormone that acts on the growth hormone secretagogue receptor 1a (GHS-R1a) (Non Patent Literature 2) and increases the secretion of growth hormone (GH) from the pituitary gland.
Ghrelin was initially isolated and purified from rats as an endogenous GHS-R ligand for GHS-R1a. Later, ghrelin amino acid sequences that are similar to the rat ghrelin in primary structure were found in vertebrates other than rats, for example, humans, mice, pigs, chickens, cattle, horses, sheep, dogs, cats, etc. (Patent Literature 1).
Desacyl ghrelin is a peptide generated through removal of the fatty acid from ghrelin. Desacyl ghrelin has almost no affinity to GHS-R1a and thus exhibits almost no activity to increase the secretion of growth hormone (GH) from the pituitary gland (Broglio, F. et al., J. Clin. Endocrinol. Metab., 89: 3062-5 (2004)). Desacyl ghrelin has also reported to exert an anorexigenic action (Perboni, S. & Inui, A., Clin. Nutr., 29: 227-34 (2010)). The actions of desacyl ghrelin are understood to be independent from GHS-R1a (Delhanty, P J. et al., PLoS One, 5: e11749 (2010)), but the receptors, physiological functions, etc. largely remain unknown.
Desacyl ghrelin, as with ghrelin, has also been reported to exert a cardioprotective activity through inhibition of apoptosis of cardiomyocytes (Non Patent Literature 3) and has been suggested to play a role in the fate of cells such as cell growth and cell death. Desacyl ghrelin also has been reported to exert an inhibitory action against the growth of prostate tumor cells (Non Patent Literature 4). Thus desacyl ghrelin is considered to act on receptors other than GHS-R1a. The reported effects of desacyl ghrelin on ingestive action include both enhancing and suppressing effects and overexpressed desacyl ghrelin results in a reduced level of IGF-1 and a small body size (Non Patent Literature 5).
Recent studies have also revealed that ghrelin increases appetite, that subcutaneous administration of ghrelin increases body weight and fat gain (Non Patent Literature 6, 7, and 8), and that ghrelin has the effect of improving the cardiac performance etc. (Non Patent Literature 9). Ghrelin also has GH secretion-promoting and appetite-increasing actions and hence has a potential to more effectively induce, through increasing appetite, GH's action of burning fat and converting it into energy or GH's anabolic action of increasing muscles (Non Patent Literature 10). Another potential of ghrelin to exert a hypothermic effect is disclosed in a patent application, although no Example is described for it (Patent Literature 2).
The inventors found that ghrelin and desacyl ghrelin exist in the amniotic fluid of pregnancy mother animals, investigated their functions and roles and, as a result, discovered that GHS-R1a exists in fetal skin cells and that desacyl ghrelin has a proliferative action for fetal skin cells (Non Patent Literature 11). As other desacyl ghrelin's actions, the effects on cancer cell growth etc. have been suggested (Non Patent Literature 12).